Visceral fat-specific regulation of plasminogen activator inhibitor-1 in aged septic mice

Maria E.C. Bruno, Sujata Mukherjee, Arnold J. Stromberg, Hiroshi Saito, Marlene E. Starr

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our previous work demonstrated that visceral adipose tissues (VAT) are a major source of PAI-1, especially in the aged (murine endotoxemia), that circulating PAI-1 protein levels match the trajectory of PAI-1 transcript levels in VAT (clinical sepsis), and that PAI-1 in both VAT and plasma are positively associated with acute kidney injury (AKI) in septic patients. In the current study utilizing preclinical sepsis models, PAI-1 tissue distribution was examined and cellular sources, as well as mechanisms mediating PAI-1 induction in VAT, were identified. In aged mice with sepsis, PAI-1 gene expression was significantly higher in VAT than in other major organs. VAT PAI-1 gene expression correlated with PAI-1 protein levels in both VAT and plasma. Moreover, VAT and plasma levels of PAI-1 were positively associated with AKI markers, modeling our previous clinical data. Using explant cultures of VAT, we determined that PAI-1 is secreted robustly in response to recombinant transforming growth factor β (TGFβ) and tumor necrosis factor α (TNFα) treatment; however, neutralization was effective only for TNFα indicating that TGFβ is not an endogenous modulator of PAI-1. Within VAT, TNFα was localized to neutrophils and macrophages. PAI-1 protein levels were fourfold higher in stromal vascular fraction (SVF) cells compared with mature adipocytes, and among SVF cells, both immune and nonimmune compartments expressed PAI-1 in a similar fashion. PAI-1 was localized predominantly to macrophages within the immune compartment and preadipocytes and endothelial cells within the nonimmune compartment. Collectively, these results indicate that induction and secretion of PAI-1 from VAT is facilitated by a complex interaction among immune and nonimmune cells. As circulating PAI-1 contributes to AKI in sepsis, understanding PAI-1 regulation in VAT could yield novel strategies for reducing systemic consequences of PAI-1 overproduction.

Original languageEnglish
Pages (from-to)706-719
Number of pages14
JournalJournal of Cellular Physiology
Volume237
Issue number1
DOIs
StatePublished - Jan 2022

Bibliographical note

Funding Information:
The authors also gratefully acknowledge the Markey Cancer Center Research Communications Office for illustrative expertise. This study was supported by NIH grants R01GM129532 and R56AG061508 (awarded to MES) and R01 GM126181 and R01AG055359 (awarded to H. S.).

Funding Information:
The authors also gratefully acknowledge the Markey Cancer Center Research Communications Office for illustrative expertise. This study was supported by NIH grants R01GM129532 and R56AG061508 (awarded to MES) and R01 GM126181 and R01AG055359 (awarded to H. S.).

Publisher Copyright:
© 2021 Wiley Periodicals LLC

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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